2.2. Introduction of TFIIH
TFIIH is a multifunctional 10-subunit protein complex integral to both NER and transcription. The TFIIH complex includes a 7-subunit core, which consists of XPB, XPD, p52, p8, p62, p34, and p44, and a three-subunit cyclin activated kinase (CAK) module, which consists of CDK7, cyclin H, and MAT1 (Tsutakawa et al., 2020) (Figure 1 ). During transcription, TFIIH is part of the preinitiation complex (PIC) and functions for promoter opening and RNA Pol II phosphorylation. The XPB subunit in TFIIH, an ATP-dependent DNA translocase, is particularly important for opening promoter DNA (Dienemann et al., 2019; Fishburn et al., 2015). The CAK kinase module in TFIIH phosphorylates Ser5 in RNA Pol II C-terminal domain to stimulate promoter escape of Pol II from the initiator element (Helenius et al., 2011; Wong et al., 2014).
However, when damage is recognized by NER surveillance proteins, UV-DDB and XPC, or the stalling of RNA Pol II, TFIIH is reallocated to damage for the NER pathway and there will be a decrease in TFIIH transcriptional activity until the damage is repaired (Coin et al., 2008). Different from its role in transcription, TFIIH mainly performs the helicase function to keep open the DNA bubble, and facilitate recruitment of downstream repair proteins. The helicase function is solely dependent on the 7-subunit core complex, but does not require the CAK kinase module. Interestingly, it has been shown that CAK needs to be displaced from TFIIH by XPA, and the displacement activates the repair function of TFIIH (Coin et al., 2008). CAK has been shown to negatively regulate the helicase activity of XPD and also phosphorylate one or more TFIIH and NER components (Araújo et al., 2000). Therefore, dissociation of the CAK complex from the TFIIH core can stimulate the helicase and ATPase activities of other subunits, allowing for the DNA strand to be opened and enlarged around the site of damage (Winkler et al., 2001). On the other hand, the p44 subunit interacts with XPD and can enhance XPD’s ATPase activity in vitro (Dubaele et al., 2003).